Abstract
The HIV-infected population is at a dramatically increased risk of developing pulmonary arterial hypertension (PAH), a devastating and fatal cardiopulmonary disease that is rare amongst the general population. It is increasingly apparent that PAH is a disease with complex and heterogeneous cellular and molecular pathologies, and options for therapeutic intervention are limited, resulting in poor clinical outcomes for affected patients. A number of soluble HIV factors have been implicated in driving the cellular pathologies associated with PAH through perturbations of various signaling and regulatory networks of uninfected bystander cells in the pulmonary vasculature. While these mechanisms are likely numerous and multifaceted, the overlapping features of PAH cellular pathologies and the effects of viral factors on related cell types provide clues as to the potential mechanisms driving HIV-PAH etiology and progression. In this review, we discuss the link between the DNA damage response (DDR) signaling network, chronic HIV infection, and potential contributions to the development of pulmonary arterial hypertension in chronically HIV-infected individuals.
Highlights
The continued development and global implementation of combinatorial anti-retroviral therapy, widely known as highly active anti-retroviral therapy (HAART), has been largely successful in reducing the burden of deadly opportunistic lung infections in immunocompromised HIV-infected patients
Concomitant with the increased longevity afforded by HAART, has been a dramatic increase in the prevalence of non-infectious cardiopulmonary disease, and pulmonary arterial hypertension (PAH) is among the most prevalent of these diseases associated with long term HIV infection [1]
HIV transgenic animal models exhibit pulmonary arterial remodeling and increased vascular resistance, demonstrating that a replication competent virus is not necessary for development of a PAH phenotype [5,6]. These findings have led the field to focus on a number of soluble HIV factors that are known to be released into circulation during HIV infection, the most heavily implicated factors being negative factor (Nef), glycoprotein (Gp120) and the transactivator of transcription (Tat)
Summary
The continued development and global implementation of combinatorial anti-retroviral therapy, widely known as highly active anti-retroviral therapy (HAART), has been largely successful in reducing the burden of deadly opportunistic lung infections in immunocompromised HIV-infected patients. HIV-PAH, like idiopathic PAH (iPAH), involves the progressive remodeling of the small pulmonary arteries, characterized by neo-intimal endothelial hyperplasia, medial smooth muscle cell hypertrophy and arterial muscularization [4]. Despite these similarities, the exact mechanisms by which HIV drives the progression of PAH remain poorly defined. Despite the established prevalence of HIV-PAH, the exact mechanisms by which HIV infection contributes to the development of cellular pathologies associated with PAH have remained elusive. We discuss the role of DNA damage response (DDR) signaling, with an emphasis on DNA damage checkpoint induction, in the molecular pathophysiology of HIV-PAH
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